Hippocampal-Sparing Radiation Therapy in Primary Sinonasal and Cutaneous Tumors of the Head and Neck

Purpose Patients with primary sinonasal and cutaneous head and neck (H&N) malignancies often receive meaningful radiation dose to their hippocampi, but this not a classic avoidance structure in radiation planning. We aimed to characterize the feasibility and tradeoffs of hippocampal-sparing radiation therapy (HSRT) for patients with primary sinonasal and cutaneous H&N malignancies. Methods and Materials We retrospectively selected patients who were treated definitively for primary sinonasal or cutaneous malignancies of the H&N at an academic medical center. All received (chemo)radiation alone or adjuvantly and substantial radiation dose to 1 or both hippocampi. We created new HSRT plans for each patient with intensity modulated radiation therapy using the original target and organ-at-risk (OAR) volumes. Hippocampi were contoured based on Radiation Therapy Oncology Group guidelines and reviewed by a neuroradiologist. Absolute and relative differences in radiation dose to the hippocampi, planning target volumes (PTVs), and OARs were recorded and compared. Results There were 18 sinonasal and 12 cutaneous H&N primary tumors (30 patients in total). Median prescription dose was 6600 cGy (range, 5000-7440 cGy), and 14 of the 30 patients received 120 cGy/fraction twice daily, 13 of the 30 patients received 200 cGy/fraction once daily, whereas others received 180-275 cGy/fraction once daily. The relative decrease in ipsilateral hippocampal Dmax and D100% using HSRT was 44% (median, 2009 cGy from 3586 cGy) and 65% (median 434 cGy from 1257 cGy), respectively. There were no statistically significant or clinically meaningful differences in PTV V100%, PTV D1%, or radiation dose to other OARs between HSRT and non-HSRT plans. Conclusions HSRT is feasible and results in meaningful dose reduction to the hippocampi without reducing PTV coverage or increasing dose to other OARs. We suggest target hippocampal constraints of Dmax < 1600 cGy and D100% < 500 cGy when feasible (without compromising PTV coverage or impacting other critical OARs). The clinical significance of HSRT in patients with primary H&N tumors should be investigated prospectively.


Introduction
Radiation therapy represents a cornerstone of therapy for patients with primary head and neck malignancies, whether definitively for those that are locally advanced or Sources of support: This work had no specific funding.All data generated and analyzed during this study are included in this published article (and its supplementary information files).Data will be made available on request.
*Corresponding author: Jacob Hall, MD; Email: jacob.hall@unchealth.unc.edu https://doi.org/10.1016/j.adro.2024.1015882452-1094/© 2024 The Author(s).Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). in locations that are not amenable to surgical resection (eg, the nasopharynx or certain sinonasal cavity tumors) or adjuvantly for patients with higher-risk pathologic features.2][3] Despite these advances, patients still often experience bothersome toxicity related to radiation therapy.5][6][7][8] Several studies have investigated cognitive decline in patients with head and neck cancer treated with definitive radiation therapy, 2 of which report results using IMRT and suggest a correlation between cognitive decline and radiation therapy dose to the temporal lobes. 4,5he hippocampus is a structure in the medial temporal lobe that is known to be important for learning and memory and has demonstrated regenerative capacity, even throughout adulthood. 9,102][13] Prospective studies have demonstrated an improvement in various measures of cognitive function when limiting radiation dose to the hippocampi for primary or metastatic brain tumors. 14,15owever, the hippocampi are not intentionally avoided with radiation during trials studying the benefits of IMRT compared with 3-dimensional conformal radiation therapy in head and neck cancer 1,2 and are not routinely avoided as part of standard head and neck cancer radiation therapy.
The hippocampus receives a clinically significant dose of radiation during a typical radiation therapy course for certain head and neck primary tumors.7][18] Several retrospective studies have demonstrated the feasibility of avoiding the hippocampi during IMRT planning without compromising target volume coverage.8][19][20][21] However, studies demonstrating feasibility for primary skin malignancies located in the head and neck and sinonasal tumors are lacking, to our knowledge.Sharma et al 22 studied late neurocognitive functioning in patients with sinonasal cancer treated with radiation and found a correlation between hippocampal dose and memory and executive function.This suggests efforts to limit radiation dose to the hippocampus may improve late neurocognitive function in these patients.
Our retrospective cohort includes patients with primary sinonasal and cutaneous tumors of the head and neck.Our objective was to demonstrate the feasibility of reducing radiation dose to the hippocampi without compromising target coverage or significantly increasing dose to other traditionally avoided organs-at-risk (OAR) in this cohort.

Patient selection
This retrospective case series was approved by the institutional review board (The University of North Carolina IRB) and performed at a single institution.We retrospectively selected patients with primary sinonasal and cutaneous tumors of the head and neck treated with definitive or postoperative radiation therapy based on diagnosis codes.Each patient received photon radiation at our institution from 2017-2021.We aimed to include 30 total patients representing a variety of tumors fitting these criteria.Each patient included received D1% of >16 Gy and/or D100% of >5 Gy to 1 or both hippocampi, which was felt to be a significant dose considering these constraints have been or are being prospectively studied.For patients with primary skin malignancies, the tumor was generally located at a similar axial level as the hippocampi, which caused the hippocampi to receive significant radiation dose.Generally, cutaneous tumors for patients fitting these criteria were located on the forehead, ears, and temporal regions.Patients with primary skin malignancies treated with electrons were excluded given the limited dose range of electrons and subsequent limited dose to the hippocampus.

Radiation planning-previous treatment and hippocampal avoidance
For radiation treatment planning, targets and OARs were contoured and IMRT plans were created using RayStation (RaySearch Laboratories).Hippocampi were not contoured or avoided as part of original treatment planning.We retrospectively contoured the bilateral hippocampi after identifying patients and original radiation plans for the study.Contours for previous target volumes and OARs were unchanged.For patients with magnetic resonance imaging (MRI) available, T1-weighted diagnostic brain MRI scans were rigidly fused to the computed tomography (CT) simulation scan at the time of initial treatment planning.Hippocampi were contoured based on the Radiation Therapy Oncology Group (RTOG) hippocampal atlas, and no planning OAR volume was used.In cases when MRI was not available, the hippocampi were contoured using CT simulation scan only.IMRTbased hippocampal-sparing radiation therapy (HSRT) plans were created with target coverage being the top priority while limiting radiation dose to the hippocampi without substantially increasing dose to other OARs.

Analysis
We compared radiation doses with the ipsilateral or contralateral hippocampi between the initial plan and HSRT plan using D max and D100% (defined as the minimum dose delivered to 100% of the contoured hippocampal volume).We used D1% to represent D max .All contoured hippocampal volumes were sufficiently small such that 1% of the contoured volume was <0.03 mL, which is commonly used to define D max .In the study by Brown et al 15 in which they measured cognitive outcomes following hippocampal avoidance whole brain radiation therapy, D0.03 mL was used to define D max .The ipsilateral hippocampus was defined as the hippocampus receiving the highest radiation dose between the 2. We also compared PTV coverage and dose with other OARs that are standardly measured at our institution.These included the standard-risk and high-risk (HR) PTV (HR PTV) V100%, HR PTV D1%, parotid mean dose, lacrimal mean dose, lens D max , optic nerve D max , optic chiasm D max , cochlea mean dose, brainstem D max , whole brain mean dose, and whole brain D max .V100% was defined as the volume of the target volume receiving 100% of the prescription radiation dose.For bilateral OARs, the dosimetric variable was averaged for the left and right structures.This averaged value was used to compare OAR doses between HSRT and non-HSRT.A paired samples t test was used to compare hippocampal D mean , D max , and D100%, dosimetric variables for other OARs, and HR PTV V100% and PTV D1% between the original and HSRT plans.

Results
We included 30 patients in our analysis.The median age at the time of radiation was 65 years (range, 27-88 years).Eighteen of these patients had primary sinonasal tumors, and 12 had primary cutaneous tumors of the head and neck.Twelve of 18 primary sinonasal tumors were histologies with applicable T staging, and the distribution is in Table 1.Sixteen patients (53%) had MRI available for contouring, while the simulation CT was used for hippocampal contouring in the remaining 14.For those with MRI available, the median bilateral hippocampal volume was 1.6 mL (range, 0.8-2.6 mL).For patients for whom CT-based contouring was used, the median bilateral hippocampal volume was 1.9 mL (range, 0.7-3.4mL).The median HR PTV for all patients was 164.5 mL (range, 51-1321 mL).Twenty-five of 30 patients were also treated with standard-risk volumes.Median standard-risk PTV was 628 mL (range, 262-1817 mL).
The most common prescription radiation dose and fractionation was 60 Gy in 30 fractions.Additional patient characteristics are displayed in Table 1.
There was a relative decrease in ipsilateral hippocampus median D mean , D max , and D100% of 56%, 44%, and 65% (P <.001), respectively, using HSRT compared with the original plan.The relative decrease of contralateral hippocampus median D mean , D max , and D100% was 50%, 45%, and 50% (P <.001), respectively, using HSRT compared with the original plan.Absolute median values are displayed in Table 2. Thirteen of the 30 (43%) and 24 of the 30 (80%) patients achieved D max of ≤16 Gy with HSRT for ipsilateral and contralateral hippocampi, respectively.Nineteen of the 30 (63%) patients and 28 of the 30 (93%) patients achieved D100% of ≤5 Gy with HSRT for ipsilateral and contralateral hippocampi, respectively.Figures 1 and 2 illustrate the improvement in hippocampal dose distribution using HSRT for a patient with postauricular basal cell carcinoma treated with postoperative radiation therapy (Fig. 1) and a patient with Abbreviations: MRI = magnetic resonance imaging.
cT4N0M0 squamous cell carcinoma of the left frontal sinus treated with concurrent chemoradiation following induction chemotherapy (Fig. 2).There were no significant differences in dosimetric variables describing PTV radiation dose between HSRT and non-HSRT plans.For all OAR dosimetric variables measured, only the median lacrimal glands mean dose and median whole brain D max increased (by 2.4% and 1.2%, respectively) following HSRT when compared with the original plan.Median dosimetric variables for all other OARs decreased on average by 4.6% to 10%.Absolute values with ranges and relative changes are displayed in Table 3.

Discussion
The hippocampi often receive meaningful radiation dose in patients receiving definitive or adjuvant (chemo) radiation therapy for certain tumors of the head and neck, particularly primary nasopharyngeal, sinonasal, and cutaneous tumors of the head and neck.Previous series have demonstrated meaningful hippocampal radiation dose in primary nasopharyngeal tumors and have shown the feasibility of HSRT. 17,18,21,24We demonstrated similar findings in our study: hippocampi receive meaningful radiation dose when treating locally advanced sinonasal and cutaneous tumors of the head and neck.Second, and more importantly, it is feasible to limit this radiation dose below constraints used in prospective protocols without comprising target coverage or significantly increasing dose to other traditionally measured OARs.Abbreviations: HR = high risk; HSRT = hippocampal-sparing radiation therapy; PTV = planning target volume; SR = standard risk.

Preclinical models have demonstrated the sensitivity of cells involved in hippocampal function to radiation and
Figure 1 A patient with a cutaneous basal cell carcinoma of the postauricular region: (A) radiation therapy plan without HSRT; (B) radiation therapy plan with HSRT.
subsequent cognitive dysfunction, even with low doses. 23,25onje et al 11 found there was inhibition of precursor proliferation and neurogenesis in a mouse model following whole brain radiation therapy (WBRT).One study showed apoptosis of proliferating stem cells responsible for neurogenesis in the hippocampus following a single 10-Gy dose in rats, and another showed human neural stem cells are sensitive to even lower doses (<10 Gy). 12,13Although the clinical impact of low-dose radiation to these cells has not been demonstrated, the sensitivity of cells related to hippocampal function to low-dose radiation has.Moving to more clinically applicable studies, there are few prospective clinical trials measuring the cognitive benefit of HSRT at various radiation doses.Gondi et al 14 showed worse delayed verbal recall in patients who received an equivalent dose in 2-Gy fractions of >7.3 Gy to 40% of the bilateral hippocampi in a prospective study.The randomized study by Brown et al 15 also showed improved cognitive function in patients receiving hippocampal avoidance WBRT plus memantine versus those receiving standard WBRT plus memantine.Hippocampal dose constraints in the study by Brown et al 15 were D100% of ≤9Gy and D max (0.03 mL) of ≤16Gy for the bilateral hippocampi.In a recent prospective protocol investigating hippocampal avoidance in low-grade gliomas, investigators selected D100% of ≤5 cobalt gray equivalents. 23Our hippocampal dose constraints were selected based on dose constraints from the abovementioned prospective protocols and clinical evidence. 15,23We felt limiting the radiation dose to a stricter constraint than D100% of ≤9 Gy may be beneficial in a population being treated with curative intent, especially if it is possible without negatively impacting other radiation plan metrics.

Hippocampal sparing-tradeoffs
Maintaining a constant integral dose, sparing the hippocampi will lead to increased dose elsewhere in the same axial plane.Dunlop et al 21 created hippocampal-sparing radiation plans for 10 patients with primary nasopharyngeal cancer and demonstrated this phenomenon.Dose difference maps from this study showed radiation dose increases along the midline, bilateral anterolateral temporal lobes, and in the maxillary sinuses at the axial level of the hippocampi.The increase in dose was generally ≤6 Gy, which is unlikely to be clinically significant. 21However, this has not been confirmed prospectively and may be more of a concern in cases where doses to the temporal lobes exceed 60 Gy and increase the risk of radionecrosis.We know limiting hippocampal radiation dose improves cognitive function to some extent, but limiting radiation dose in other regions of the temporal lobe may also affect cognitive function.Further determining which regions of the brain are less affected by radiation and have a smaller effect on cognition is integral to optimizing cognitive function following radiation, rather than simply avoiding the hippocampus.
Our study showed statistically significant reductions in hippocampal median D mean , D max , and D100% for both ipsilateral and contralateral sides without compromising target coverage or increasing other OAR radiation dose.There were statistically significant reductions in other OAR radiation doses using HSRT (aside from the hippocampi), but we do not intend to portray HSRT as a method for doing so.These changes were small and clinically insignificant.HR PTV V100% was 95% for both the original and HSRT plans.We expect this and acknowledge this is a result of prespecified IMRT goals in planning.We feel that HSRT for head and neck primary tumors should routinely be considered even without prospective evidence proving HSRT improves cognitive outcomes in this population, given the very low risk, minimal effort, and potential benefit demonstrated in other patient populations of doing so.The hippocampi are rarely an atrisk region of cancer spread in this population.This recommendation assumes target coverage is maintained and radiation dose to other OARs is not significantly different, including confirming clinically acceptable dose to the anterior temporal lobes.

Limitations
We acknowledge that the dose constraints used in our study were the same for every patient, regardless of prescription dose and number of fractions.We felt this allowed for additional simplicity because the goal of this study was to demonstrate feasibility rather than to measure cognitive function.Should the benefits of HSRT in patients with head and neck tumors be studied prospectively, we recommend the dose constraints account for the dose and number of fractions being used in the study.In addition, the D max of ≤16 Gy constraint used in this study was based on a radiation dose and fractionation schedule different from most head and neck cancer treatments (total 30 Gy over 10 fractions) but was satisfied for many patients in our study.Should this be adjusted for typical head and neck plans, which often use 30 fractions when conventionally fractionated, the dose constraints would be even less difficult to meet.Another consideration when adjusting dose constraints from a 10-fraction plan to longer, 30+-fraction daily plans or 50+-fraction twice daily plans is that the linear-quadratic model used to calculate equivalent dose in 2-Gy fractions does not account for time.
An additional limitation is that a portion of the patients in this study did not have brain MRI available for hippocampal contouring, requiring us to use the simulation CT.The hippocampal contours were typically larger when using the CT given the anatomic uncertainty, which would theoretically make it more difficult to meet hippocampal constraints.However, there may be some situations where anatomic inaccuracies caused by hippocampal contouring on CT could lead to a misleading, more favorable position of the hippocampal contour relative to high radiation dose.In this study, hippocampal contours (including those contoured on the simulation CT without MRI) were reviewed and edited by a board-certified neuroradiologist (BH) at our institution (example CT-based hippocampal contours in Fig. E1).

Conclusions
Limiting radiation dose to the hippocampi can reduce the risk of neurocognitive decline.Definitive and adjuvant (chemo)radiation for primary sinonasal and skin cancers in the head and neck can deliver substantial incidental dose to the hippocampi.We demonstrated feasibility in limiting radiation dose to the hippocampi below previously validated constraints used for WBRT without comprising target coverage or increasing meaningful dose to other OARs.This simple and resource-efficient technique should be used when the hippocampi may receive substantial incidental radiation dose in effort to minimize neurocognitive toxicity.Better quantification of neurocognitive toxicity because of hippocampal radiation for head and neck primary tumors should be studied prospectively to allow physicians and patients to understand better the benefits of HSRT.

Disclosures
Colette Shen reports research support from AstraZeneca (not related to this work) and is a consultant for Nanobiotix and GT Medical Technologies (unrelated to this work).All authors except for Lorie Nguyen are employed by the University of North Carolina.

Figure 2 A
Figure 2 A patient with a primary sinonasal malignancy: (A) radiation therapy plan without HSRT b) radiation therapy plan with HSRT Abbreviations: HSRT = hippocampal-sparing radiation therapy.

Table 1
Patient and tumor characteristics

Table 2
Differences in radiation dose variables of the hippocampi and PTV with and without HSRT

Table 3
Differences in radiation dose variables of OARs